The drug abuse problem in general and the widespread use of marijuana, in particular, have focused attention on the chemistry and pharmacology of the plant Cannabis Sativa. In the decade since the discovery of the cannabinoid receptors, much progress has been made in the cannabinoid field. It has been established that there are at least two types of cannabinoid receptors; CB1 receptors which are present both inside and outside the central nervous system (CNS) and CB2 receptors which are found mainly in the periphery. Two main endogenous ligands have been discovered, anandamide (AEA) and 2-arachidonylglycerol (2-Ara-G1). Also known as endocannabinoids, they are both present in central as well as peripheral tissues. The long term goal of this program is to develop Structure Activity Relationships (SAR) of AEA which are eicosanoids, and bear no chemical/structural relationship to other cannabinoids. We feel that SAR of AEA will be critical for understanding how AEA and other cannabinoids interact with the same receptor. Our specific aims are (i) to continue to examine the SAR of arachidonic acid portion of AEA (ii) to develop AEA/THC (tetrahydrocannabinol) hybrids (iii) to develop novel anandamide membrane transporter (AMT) probes and (iv) to synthesize hydroxylated AEA analogs as potential metabolites of AEA. The synthesis of these analogs and their subsequent biological evaluation will provide us with more potent agonists, partial agonists and antagonists in the AEA series. This may result in the discovery of a silent antagonist with an AEA template and could lead to the discovery of other cannabinoid subtype receptors, reveal mechanisms involved in brain function, and lead to the development of therapeutic drugs in the areas of inflammation, pain, vasodilation, antitumor therapy and other CNS related diseases. The proposed study will increase our understanding of the pharmacological action of this important class of compounds, leading to the discovery of new drugs for the health care field.